This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Imatinib mesylate treatment induces complete cytogenetic remissions &#40;CCR&#41;in the majority of CML patients and results in significantly improved survival and is currently the front-line treatment for CML. However, most patients continue to have evidence of persistent residual disease detectable by PCR analysis, and there are several lines of evidence that residual BCR-ABL+ stem cells may persist in CML patients despite imatinib treatment. Therefore patients may require to be treated with imatinib indefinitely and may remain at risk of relapse, and measures to enhance elimination of residual disease are needed to further improve outcomes and effect cure of leukemia. In preclinical studies the combination of the HDAC inhibitor LAQ824 with imatinib results in significantly enhanced apoptosis of CML primitive progenitors compared to imatinib or LAQ824 alone. A very similar HDAC inhibitor LBH589 is in early clinical trials and has been well tolerated. These results provide a strong rationale for testing whether addition of LBH589 to imatinib can enhance elimination of residual BCR-ABL+ stem/progenitor cells in imatinib-treated CML patients in CCR. We propose to perform a phase 1 study to determine the LBH589 dose which can be safely used in combination with imatinib. Since imatinib monotherapy is associated with an excellent prognosis, LBH589 dose escalation will be limited to a maximal dose that is known to be well tolerated based on current LBH589 monotherapy trials to reduce risk of potential toxicity. A Phase 2 study will be planned to follow.